AP Syllabus focus:
‘Internal controls and checkpoints regulate progression through the cell cycle, ensuring key processes are completed before division continues.’
Cells do not move through the cell cycle automatically. They rely on regulatory systems that monitor cell size, DNA integrity, and chromosome attachment, pausing or stopping division until conditions are correct.
What checkpoints do
Cell cycle regulation depends on checkpoints that act like control gates.
Three internal checkpoints (G1, G2, and M) mapped onto the cell cycle. The figure highlights what each checkpoint tests before the cell is allowed to proceed: DNA integrity at G1, completion/quality of DNA replication at G2, and correct kinetochore attachment to spindle fibers at the metaphase (M) checkpoint. This provides a high-level “control logic” view of how cells enforce order and fidelity during division. Source
At each gate, the cell integrates information from internal sensors and external cues to decide whether to proceed, pause for repairs, or exit the cycle.
Cell cycle checkpoint: A control point where regulatory molecules assess whether critical events (e.g., DNA replication or spindle attachment) are correctly completed before the cell proceeds.
Two major control principles
Order: Later events do not start until earlier events are complete (e.g., mitosis does not begin until DNA is fully replicated).
Fidelity: Errors are detected and corrected to protect genome stability (e.g., DNA damage triggers delays for repair).
Major checkpoints in eukaryotic cells
G1 checkpoint (often called the restriction point)
This checkpoint determines whether the cell commits to DNA replication and division.
Key questions assessed:
Is the cell large enough, with adequate nutrients and energy?
Are growth conditions favorable (e.g., appropriate growth signals)?
Is DNA undamaged?
Possible outcomes:
Proceed into S phase if conditions are met.
Pause in G1 to grow or repair.
Enter a nondividing state (often termed G0) if division is not appropriate.
G2 checkpoint
This checkpoint occurs after DNA replication and before mitosis.
Key questions assessed:
Was DNA replication completed?
Is replicated DNA free of major damage?
Common response:
Delay progression into mitosis while DNA repair pathways correct problems.
If damage is extensive, progression can be blocked to prevent distributing faulty genomes to daughter cells.
M checkpoint (spindle assembly checkpoint, during metaphase)
This checkpoint ensures accurate chromosome segregation.
Key questions assessed:
Are all chromosomes properly attached to the mitotic spindle via kinetochores?
Are chromosomes correctly aligned so sister chromatids can separate evenly?
If attachment is incorrect:
The cell delays anaphase onset, reducing the risk of nondisjunction (unequal chromosome distribution).
Internal controls that enforce checkpoints
Checkpoint function depends on regulatory proteins that switch key cell-cycle events on or off and on sensor pathways that detect problems.
Sensing and signalling problems
DNA damage sensors detect breaks or replication stress and initiate signalling cascades.
Spindle attachment sensors detect tension and attachment status at kinetochores.
Cell size and resource sensors integrate ATP availability and biosynthetic capacity.
Typical regulatory outcomes
Cell-cycle arrest: Temporary pause that keeps the cell in the current phase.
DNA repair activation: Recruitment of repair enzymes to restore correct DNA sequence/structure.
Inhibition of progression machinery: Blocking activation of processes required for the next stage (for example, preventing entry into mitosis until replication is complete).
Tumour-suppressor roles (checkpoint enforcement)
Some genes encode proteins that function as “brakes” on division.
p53 can promote cell-cycle arrest when DNA damage is detected, helping prevent replication of damaged DNA.
Rb (retinoblastoma protein) helps restrict progression through G1 when conditions are not favourable. Loss or inactivation of these controls undermines checkpoint reliability and increases the chance that cells divide with errors.
Why checkpoints matter for organismal function
Checkpoint regulation supports:
Developmental accuracy: Correct proliferation patterns require reliable start/stop decisions.
Tissue maintenance: Dividing cells must duplicate and partition genomes precisely.
Genome stability: Preventing the inheritance of DNA damage preserves long-term cell function across many divisions.
FAQ
Unattached kinetochores assemble inhibitory complexes that block anaphase-promoting activity.
Once attachment and tension are correct, inhibitory signalling stops and anaphase can proceed.
Cells treated with spindle poisons (e.g., disrupting microtubules) arrest in metaphase rather than entering anaphase.
Similarly, inducing DNA breaks causes delayed entry into S phase or mitosis.
Cell type and context affect dependence on external growth factors.
Highly regenerative tissues often receive strong pro-growth cues, whereas differentiated cells tend to require stricter signalling to re-enter division.
Checkpoint pathways use thresholds: minor issues may slow progression, while severe defects cause prolonged arrest.
This balances genome protection with maintaining tissue renewal.
If the spindle checkpoint is weakened, cells may enter anaphase with incorrect attachments.
This increases nondisjunction risk, producing daughter cells with abnormal chromosome numbers (aneuploidy).
Practice Questions
State one function of the G2 checkpoint. (1 mark)
Ensures DNA replication is complete and/or checks for DNA damage before mitosis; allows time for repair. (1)
A cultured eukaryotic cell has DNA damage and also shows several chromosomes not attached to spindle fibres. Explain how checkpoints could regulate progression through the cycle in this situation. (5 marks)
DNA damage activates checkpoint signalling causing cell-cycle arrest (G1 or G2). (1)
Arrest provides time for DNA repair mechanisms to act before replication/mitosis proceeds. (1)
G2 checkpoint prevents entry into mitosis if replication is incomplete or DNA is damaged. (1)
Spindle assembly checkpoint delays anaphase until kinetochores are correctly attached/aligned. (1)
Prevents mis-segregation/nondisjunction and reduces propagation of mutations to daughter cells. (1)
